The first application of positron annihilation radiation for medical imaging followed by the development of the first human Positron Emission Tomography (PET) scanner were milestones in the deployment of PET imaging as we know it today. Further technological developments coupled with the appearance of radiopharmaceuticals, perhaps most notoriously [18F]-2-fluorodeoxy-D-glucose, firmly established PET as a non-invasive imaging modality. Today PET is used routinely in the clinic to diagnose a range of cancers, neurological disorders and cardiovascular diseases. It has become a useful tool to facilitate drug discovery and development by enabling a new kind of precision pharmacology. These applications have created a demand for new radiochemistry with a focus on [18F]fluorination, a choice driven by the advantageous properties of 18F as a positron emitter and the prevalence of fluorine substitution in drug design.
Molecules labelled with the unnatural isotope fluorine-18 are used as radiotracers for positron emission tomography. Typical challenges associated with 18F radiochemistry are the short half-life of 18F (<2 h), the use of sub-stoichiometric amounts of 18F, relative to the precursor and other reagents, as well as the limited availability of 18F sources of suitable reactivity ([18F]F− and [18F]F2). An important challenge in [18F]radiochemistry is the labelling of (hetero)arenes not amenable to SNAr with [′T]F−. In the ideal case, the [18F]fluorination of these most demanding substrates would be performed with broadly used potassium [18F]fluoride from shelf-stable readily available precursors applying a protocol amenable to automation.
In the past decade, the number of methods available for the installation of fluorine into (hetero)arenes has increased significantly since these structural motifs are commonly found in pharmaceutical drugs to impart metabolic robustness. In contrast, the preparation of [18F]labeled (hetero)arenes that are not accessible via aromatic nucleophilic substitution with [18F]fluoride remains challenging. The reaction of diaryliodonium salts with [18F]fluoride ions has been described almost 2 decades ago (V. W. Pike et al., Chem. Soc., Chem. Commun. 21, 2215 (1995)). Although it can be applied to labeling of electron-rich, electron neutral and electron-deficient arenes with fluorine-18, this reaction has gained limited interest due to significant limitations related to the tedious preparation of diaryliodonium salts and purification of aryl by-products. Recent advances exploit the value of metal-free umpolung strategies for the direct nucleophilic [18F]fluorination of arenes under oxidative conditions, a concept successfully applied to phenol precursors (Z. Gao et al., Angew. Chem. Int. Ed. 51, 6733 (2012)). Metal-mediated processes have also emerged for direct [18F]fluorination of various substrates inclusive of arenes not suitable for SNAr. Early studies demonstrated that the [18F]NF reagent [18F]Selectfluor bis(triflate) prepared from [18F]F2, allowed for the Ag(I)-mediated electrophilic [18F]fluorination of arylstannannes (H. Teare et al., Angew. Chem. Int. Ed. 49, 6821 (2010)) and arylboronic acids (I. S. Stenhagen, A. K. Kirjavainen, S. J. Forsback, C. G. Jorgensen, E. G. Robins, S. K. Luthra, O. Solin, V. Gouverneur, Chem. Commun. 49, 1386 (2013)) within the time constraint imposed by the short half-life 18F isotope (t1/2<2 h). Currently, this chemistry is not used broadly as only a minority of PET centers in the world is equipped to produce [18F]F2, and tracers derived from [18F]F2 are of lower specific activity than those produced from [18F]fluoride. More recently, a purpose-built [18F]Pd(IV)F complex prepared from high specific activity [18F]F− but acting as a source of [18F]F+, converted Pd(II) aryl complexes, themselves obtained from the corresponding aryl boronic acids, into [18F]fluoroarenes (E. Lee et al., Science 334, 639 (2011)). Ni(II) aryl complexes prepared in two steps from aryl bromides were also found amenable to nucleophilic [18F]fluorination in the presence of an external oxidant, yielding a range of [18F]labeled arenes in up to 58% radiochemical yield (RCY) (E. Lee, J. M. Hooker, T. Ritter, J. Am. Chem. Soc. 134, 17456 (2012)). These organometallic Pd- and Ni-based precursors are not commercially available and not trivial to prepare by non-chemist professionals performing (pre)clinical PET imaging studies. These characteristics coupled with the necessity to develop automated protocols in compliance with Good Manufacturing Practice (GMP) requirements, encourage the development of alternative simpler solutions for the direct nucleophilic [18F]fluorination of (hetero)arenes from readily available shelf stable materials. Furthermore, there are toxicity concerns associated with the use of nickel and palladium.
As part of an ongoing research program in transition metal-promoted [18F]fluorination, the inventors have previously exploited the value of copper complexes in [18F]radiochemistry with the [18F]trifluoromethylation of aryl and heteroaryl iodides from [18F]CuCF3 (M. Huiban et al., Nature Chemistry 5, 941 (2013)). It is desirable to develop a mild nucleophilic [18F]fluorination of arylboron compounds with the aim to provide a general and simple method to access [18F](hetero)arenes.
Recent reports disclosing aryl-fluoride bond forming reductive elimination reactions from high valency CuIII complexes provided a focus (A. J. Hickman, M. S. Sanford, Nature 484, 177 (2012)) and the ability of pinacol-derived arylboronate esters (ArBPin) to undergo fluorination with potassium fluoride in the presence of Cu(OTf)2 served as a starting point for [18F]radiochemical development (Y., Ye, S. D. Schimler, P. S. Hanley, M. S. Sanford, J. Am. Chem. Soc. 135, 16292 (2013)).
However, translation from the fluorination of Ye et al. to no-carrier added [18F]radiochemistry presented several distinctive challenges. Firstly, since the “reverse stoichiometry” reflecting the minute quantities of fluorine (roughly 10−4 M or lower) available for labeling contrasts with the necessity to use 4 equivalents of KF to achieve reasonable chemical yields of the desired fluoroarenes in Ye et al. it was not initially expected that the process could be used for radiolabelling. Complications could also arise from sequestration of [18F]fluoride onto the boron-containing substrates used in excess. Thus, it is an object of the present invention to develop a [18F]fluorination process which can be applied to a wide range of arene and heteroarene substrates while maintaining good radiochemical yields and specific activity.